The project consists of a series of clinical trials evaluating the clinical efficacy and safety of experimental therapeutic agents for the control of acute pain and perioperative apprehension in ambulatory patients undergoing minor surgical procedures. The surgical removal of impacted third molars serves as a model of minor surgery with associated intraoperative and postoperative pain and perioperative apprehension. All studies are double-blind with randomly allocated, parallel treatment groups and multiple dependent measures of therapeutic efficacy and clinical safety. The efficacy of a low dose of a nonsteroidal anti-inflammatory drug (NSAID) ketoprofen applied peripherally at the site of injury was demonstrated in two previous clinical trials. A recent study provides evidence for a locally-mediated mechanism of action: administration into the extraction sites results not only in significantly less pain than following oral administration of the same formulation but with substantially lower blood levels of the drug. The results of these studies support the hypothesis being evaluated that peripheral administration of an NSAID at low doses results in greater analgesic efficacy and a lower incidence of side effects by minimizing systemic exposure. Two parallel studies evaluated the analgesic efficacy of a receptor antagonist of substance P. The drug is administered prior to, during, and following the surgery in an attempt to block occupancy of the substance P receptor and possible CNS activation of nociceptive processes which can persist after removal of the painful peripheral input. Results of the initial study demonstrated a transient effect at one time point in comparison to placebo, with the positive control (ibuprofen) providing a prolonged suppression of pain in the immediate postoperative time point. A subsequent study did not provide any additional evidence to support this observation, suggesting that the analgesic effects of this substance P antagonist cannot be demonstrated in the oral surgery model of acute pain. A study in progress is evaluating the analgesic efficacy of dextromethorphan, an antitussive drug which is also active as a blocker of the N-methyl-D-aspartate (NMDA) receptor. Subjects receive increasing doses of the drug over 48 hours based on side effects reported. One-third of the projected number of patients have successfully completed the study.